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Dementia is defined as cognitive decline in one or more domains (e.g., memory, language, attention, visuospatial processing, social behavior) sufficient to impair independent daily function.
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Insidious onset and gradual progression of cognitive impairment over months to years may be secondary to neurodegenerative diseases (Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia being the most common), chronic cerebrovascular disease (vascular dementia), or due to potentially treatable causes such as:
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Systemic diseases:
Metabolic deficiency: vitamin B12 deficiency
Endocrine disease: Hypothyroidism
Chronic infection: AIDS, syphilis
Obstructive sleep apnea
Medications, such as psychotropic medications in older adults
Toxins, such as alcohol or drug abuse, heavy metal poisoning
Intracranial pathology, such as tumor, chronic subdural hematoma, normal pressure hydrocephalus
Psychiatric disease, such as depression
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Neurodegenerative disease is progressive with no disease-modifying medications, and treatment is limited to symptomatic management and supportive care. Therefore, part of the initial evaluation of patients with dementia is to assess for potentially treatable causes. The history should evaluate for depression, medication history, and sleep apnea. Examination should assess for focal findings that might suggest focal underlying pathology. Mental status testing should be performed to assess for the type and extent of impairment(s), for example with the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MOCA).
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Frontal release signs may be present on physical examination in patients with dementia, but are not universally present and some of these signs can be seen in non-demented elderly patients (and occur normally in infants as does Babinski’s sign). Frontal release signs include:
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Snout reflex: the patient purses the lips when the examiner taps at the center of the lips.
Grasp reflex: the patient cannot inhibit grasping the examiner’s hand or an object when placed into the patient’s hand.
Suck reflex: the patient will attempt to suck any object (such as a pen) moved toward the mouth.
Rooting reflex: lightly touching the patient’s cheek causes the patient to turn the head toward that side.
Palmomental reflex: briskly scratching the patient’s palm causes a twitch of the ipsilateral chin.
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Laboratory evaluation for dementia should include vitamin B12, thyroid-stimulating hormone (TSH), and neuroimaging (ideally MRI). HIV and syphilis testing should be considered in patients with risk factors for these diseases. Neuroimaging may reveal an etiology of altered cognition such as malignancy (primary or metastatic), subdural hematoma, normal pressure hydrocephalus, or a characteristic pattern of atrophy associated with a particular neurodegenerative etiology. Formal neuropsychological testing can help to better characterize the nature and degree of cognitive impairment, which may be helpful both in making a diagnosis and in guiding cognitive therapy.
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The core features of the most common dementia syndromes are presented in Table 22–1. Multiple underlying pathologies frequently coexist (e.g., Alzheimer’s disease and vascular dementia). Some ask why it is important to distinguish between types of dementia clinically/radiologically when there are currently no specific disease-modifying therapies. A precise diagnosis allows for tailoring of symptomatic therapy and also aids in discussion of prognosis. In addition, clinical-radiologic diagnosis is essential to characterizing these diseases in order to improve early identification toward the goal of developing disease-modifying therapies.
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Mild Cognitive Impairment
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Mild cognitive impairment (MCI) refers to cognitive decline with preserved ability to function independently. Patients with MCI often present for evaluation due to awareness of their deficits, whereas patients with dementia are commonly brought for evaluation by family members and may be less aware of their deficits. MCI is estimated to have a risk of progression to dementia of approximately 10% per year. The most common form of MCI is amnestic MCI in which the patient has isolated memory loss, although patients may have deficits in another individual cognitive domain or multiple domains. In patients with MCI, there does not appear to be a clear benefit to using the cholinesterase inhibitors used in patients with Alzheimer’s disease (see “Treatment of Alzheimer’s Disease” below), although some practitioners will consider their use in patients in whom MCI is thought likely to be due to underlying Alzheimer’s pathology.
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Clinical Features of Alzheimer’s Disease
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Alzheimer’s disease (AD) is the most common neurodegenerative cause of dementia. In most cases, the first and most prominent cognitive deficit is in memory, specifically memory for recent events (episodic memory). Patients may forget to do things they had planned to do (e.g., miss appointments), forget having done something, or forget a conversation. Other symptoms that may also be present initially or may emerge as the disease progresses include getting lost, decreased performance at work, and word-finding difficulties. The disease progresses inexorably toward a state of global dementia with patients generally losing an average of 3 points per year on the MMSE.
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Most cases of AD are sporadic, although some are familial. Familial cases of AD usually begin at a younger age than sporadic cases. Inheritance of familial AD is autosomal dominant due to mutations in the amyloid precursor protein (APP), presenilin 1, or presenilin 2 genes that lead to overproduction of amyloid. Risk of development of Alzheimer’s disease is increased in patients with the ε4 allele of apolipoprotein E (APOE). Patients with Down’s syndrome also develop early AD since amyloid precursor protein is found on chromosome 21, and so it is present in triplicate in patients with trisomy 21.
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Posterior cortical atrophy—In posterior cortical atrophy (also called the visual variant of AD), neurodegeneration occurs specifically in parieto-occipital regions, leading to visual cognitive deficits (e.g., elements of Balint syndrome; see “Balint syndrome” in Ch. 6). The underlying pathology is most commonly Alzheimer pathology, although posterior cortical atrophy can also be caused by other types of neurodegenerative pathology.
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Neuroimaging and Laboratory Features of Alzheimer’s Disease
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MRI in AD usually demonstrates bilateral atrophy in medial temporal regions (hippocampus and entorhinal cortex) and the superior parietal lobe (Fig. 22–3). Nuclear medicine studies in AD show hypometabolism on positron emission tomography (PET) and reduced perfusion on single photon emission computed tomography (SPECT) in bilateral temporoparietal cortex, posterior cingulate cortex, and precuneus. Amyloid PET imaging to identify amyloid burden in the brain is currently mostly used in research settings (e.g., to determine eligibility for clinical trials).
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In the cerebrospinal fluid (CSF), low Aβ42 and increased tau (leading to decreased Aβ42/tau ratio) can predict underlying Alzheimer pathology in the appropriate clinical setting. Amyloid is presumably low in the CSF because it has accumulated in plaques in the brain.
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Treatment of Alzheimer’s Disease
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Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the N-methyl-d-aspartate (NMDA) antagonist memantine may provide modest symptomatic benefit in cognition in patients with AD. Gastrointestinal side effects can occur with the cholinesterase inhibitors. A common treatment strategy in patients with AD is to use a cholinesterase inhibitor initially (if tolerated), and to add memantine as patients progress to moderate/severe dementia. Otherwise, care of patients with AD is supportive.
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Dementia With Lewy Bodies
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Clinical Features of Dementia With Lewy Bodies
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Dementia with Lewy bodies (DLB) is one of the Parkinson-plus syndromes along with multiple systems atrophy, progressive supranuclear palsy, and corticobasal degeneration (see Ch. 23). These are all diseases in which there are parkinsonian symptoms along with other types of neurologic dysfunction. In addition to a dementia characterized by initial deficits in visuospatial and executive function, patients with DLB develop parkinsonism, visual hallucinations (usually nonthreatening hallucinations of people or animals), and fluctuations in attention and level of arousal. History of rapid eye movement (REM) sleep behavior disorder is common (as in other synucleinopathies; see “Nonmotor Aspects of Parkinson’s Disease” in Ch. 23), and neuroleptic sensitivity (worsened parkinsonism and/or cognition with administration of neuroleptics) and autonomic dysfunction (orthostasis, constipation, incontinence, sexual dysfunction) are frequently present.
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Patients with Parkinson’s disease (see “Parkinson’s Disease” in Ch. 23) can develop dementia over the course of the disease. DLB is generally distinguished from Parkinson’s disease dementia by the following clinical features: patients with DLB develop symptoms and signs of dementia before or simultaneously with features of parkinsonism (in Parkinson’s disease dementia, parkinsonism usually precedes dementia by years), parkinsonism in DLB is usually symmetric (in Parkinson’s disease, parkinsonism usually begins asymmetrically), parkinsonism in DLB is usually less responsive to levodopa (or may not respond at all) compared to patients with Parkinson’s disease (whose parkinsonism generally responds to levodopa).
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Neuroimaging Features of Dementia With Lewy Bodies
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There is no characteristic pattern of atrophy on structural imaging in DLB, but nuclear imaging may show hypometabolism/hypoperfusion in occipital and temporoparietal regions (compared to just temporoparietal hypometabolism/hypoperfusion in AD).
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Treatment of Dementia With Lewy Bodies
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As in AD, cholinesterase inhibitors and memantine may be useful in symptomatic management of cognitive dysfunction in DLB. As in the other Parkinson-plus syndromes, there is usually little or no response to dopaminergic therapies (in contrast to Parkinson’s disease), but if parkinsonism is a prominent disabling feature in a patient with DLB, a trial of levodopa can be considered. Symptomatic treatment can be considered for mood, REM sleep behavior disorder (clonazepam), and autonomic dysfunction.
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Frontotemporal Dementia
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Frontotemporal dementia (FTD) includes two categories of dementia syndromes: behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). As the names suggest, bvFTD is characterized by personality changes and neuropsychiatric dysfunction, and PPA is characterized by language deficits. Behavioral and personality changes in bvFTD can include anything from apathy to disinhibition, and from social withdrawal to socially deviant behavior. Patients generally lack insight into the changes in their personality and behavior. Other common features include loss of empathy, obsessive compulsive or perseverative behaviors, and executive dysfunction. PPA has three variants with particular language deficits: nonfluent/agrammatic, semantic, and logopenic (Table 22–2). Neuroimaging in FTD shows selective frontotemporal atrophy (Fig. 22-4) that may be very focal within language areas in PPA.
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The most common underlying pathologic findings in FTD are tau or TDP-43, although AD pathology is the most common underlying pathology in the logopenic variant of PPA. Some patients develop syndromes of overlap of FTD with motor neuron disease, corticobasal degeneration, or progressive supranuclear palsy. Treatment is symptomatic/supportive. Selective serotonin reuptake inhibitors (SSRIs) may be helpful in managing the psychiatric symptoms of bvFTD. Unlike patients with AD or DLB, patients with FTD do not appear to benefit from cholinesterase inhibitors.
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Vascular dementia refers to impaired cognitive function due to cerebral infarction. This may be due to accumulation of cognitive deficits from serial strokes in a stepwise manner, more insidious with chronic accumulation of subcortical microvascular disease, or some combination of the two. Clinical signs depend upon site(s) of prior infarction, but executive dysfunction and cognitive slowing are common, and focal features, upper motor neuron signs, and/or pseudobulbar affect may be present. In cases of insidious cognitive decline and evidence of both atrophy and subcortical white matter disease on neuroimaging, the differentiation between AD, vascular dementia, and overlap of the two may not be possible. There may be some benefit of cholinesterase inhibitors and memantine in vascular dementia as in AD, so a medication trial may be attempted in ambiguous or presumed overlap cases. Secondary stroke prevention is of course important as in any patient with prior stroke (see “Secondary Prevention of Ischemic Stroke” in Ch. 19).
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Normal Pressure Hydrocephalus
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Although not a neurodegenerative disease, normal pressure hydrocephalus (NPH) is discussed here since it should be considered in the differential diagnosis of patients presenting with dementia. The predominant symptoms of NPH are gait dysfunction, urinary incontinence, and dementia. In this condition, ventricular enlargement leads to frontal lobe dysfunction, and CSF diversion by ventriculoperitoneal (VP) shunt can lead to improvement. NPH may be idiopathic or can be caused by impaired CSF circulation caused by prior subarachnoid hemorrhage or meningitis.
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In most patients with NPH, gait dysfunction is the first sign of the disorder, and dementia and urinary incontinence emerge later in the course of the condition. The classic gait pattern in NPH is wide based and “magnetic”: the feet appear to be magnetically drawn back to the floor as soon as they are lifted. (Note that severe proprioceptive dysfunction due to large-fiber neuropathy, sensory ganglionopathy, or posterior column dysfunction can also cause a magnetic gait). The walking problem in NPH is due to dysfunction of higher order control of gait, and is not due to weakness or incoordination. This can be demonstrated by having the patient bicycle the legs in bed. Bicycling movements require strength and coordination and are usually normal in NPH in marked contrast to the very impaired gait.
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The diagnosis of NPH is suggested by the clinical picture in conjunction with radiologic evidence of ventriculomegaly out of proportion to cerebral atrophy. With aging and/or dementia, there is cerebral atrophy and subsequent ex vacuo dilatation of the ventricles to fill the remaining space. This must be distinguished from ventricular enlargement due to hydrocephalus. One way to quantify ventriculomegaly is to calculate the Evans ratio, calculated by measurements on axial neuroimaging. The Evans ratio is calculated by dividing the largest “wingspan” of the frontal horns of the lateral ventricles by the maximum horizontal width between the left and right inner table of the skull on the same axial slice. An Evans ratio >0.31 is considered to be consistent with NPH in the appropriate clinical context (Fig. 22–5).
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Diagnosis of NPH is made by noting improvement of gait and/or cognitive function after a large-volume lumbar puncture or continuous lumbar drainage of spinal fluid. Improvement with one of these tests suggests a likely response to placement of a VP shunt, although even some patients who do not improve with lumbar puncture or lumbar drain may still improve with a VP shunt. This leads to challenging clinical decision making since the differential diagnosis may be between AD with no disease-modifying treatment and the possibility of NPH that could respond to VP shunt (but with the inherent risks of complications of shunt placement; see “Ventriculoperitoneal Shunt” in Ch. 25). In NPH, gait dysfunction is generally more likely to improve with a VP shunt than cognitive impairment.